Significant advances have been made in the understanding of olfactory transduction using animal models. It is now generally accepted that stimulation of olfactory receptors results in G-protein-mediated activation of second messenger systems (cAMP and IP3) leading to changes in membrane conductance. This causes depolarization of the cell membrane resulting in an increased frequency of firing of action potentials that carries information to the brain. However, relatively little is known about the mechanisms of olfactory transduction at the molecular or cellular levels in humans. We propose to use viable human olfactory neurons isolated from olfactory epithelium biopsies to study the basic mechanisms of olfactory signal transduction in humans using sensitive single cell electrophysiological, biophysical and molecular biological techniques. The major goal will be to determine to what extent the second messenger hypothesis of olfactory transduction, which was proposed based solely on animal studies, applies to human olfaction. These experiment will result in the establishment of a novel model system to study normal and abnormal olfaction in humans at the cellular and molecular levels. This model system has important potential applications in clinical research of olfactory dysfunction. Alzheimer's disease, a progressive neuronal degenerative disorder which afflicts an estimated 4 million individuals in the United States causes olfactory dysfunction. The mechanisms of olfactory neuron degeneration in Alzheimer's disease are believed to be similar to those of neurons elsewhere in the brain. We will use isolated olfactory neurons obtained from Alzheimer's patients to study changes in intracellular calcium homeostasis and gene expression which could play an important role in the etiology of Alzheimer's disease.